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Peer-reviewedCC BY-NC-ND 4.0In Vivo

Macrophage-derived Exosomes Regulate Neuronal ACSL6 in Experimental Temporomandibular Disorder Pain

  • YALI ZHANG1,2
  • CHENYU FAN1
  • JINGWEN WU1
  • SHUO MU1
  • ZHUO CHEN1
  • SIYU WU1
  • XIAN WU3
  • ZHENGUO SHEN1
  • TIAN XING1
  1. 1College & Hospital of Stomatology, Anhui Medical University, Anhui Provincial Key Laboratory of Oral Diseases Research, Hefei, P.R. China
  2. 2Anhui Province Key Laboratory of Cognition and Neuropsychiatric Disorders, The First Affiliated Hospital of Anhui Medical University, Hefei, P.R. China
  3. 3Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, P.R. China
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Abstract

Background/Aim: Temporomandibular disorders (TMD) are frequently accompanied by persistent pain, but the underlying mechanisms remain incompletely understood. Macrophage-neuron communication in the trigeminal ganglion (TG) may contribute to TMD pain. This study investigated whether macrophage-derived exosomes (EXOs) promote neuronal inflammation and pain by regulating acyl-CoA synthetase long-chain family member 6 (ACSL6).

Materials and Methods: A mouse model of TMD pain was established by intra-articular injection of complete Freund’s adjuvant (CFA) into the temporomandibular joint. Pain behavior, TG histopathology, inflammatory mediator expression, and ACSL6 levels were evaluated. The effects of clodronate liposome-mediated macrophage depletion and GW4869-mediated inhibition of EXO release were examined in vivo. In vitro, conditioned medium (CM) and EXOs derived from tumor necrosis factor-alpha-activated RAW264.7 cells were applied to primary TG neurons and PC12 cells. GW4869 treatment of RAW264.7 cells, ACSL6 overexpression, and docosahexaenoic acid (DHA) supplementation were used for further functional evaluation.

Results: CFA reduced the head withdrawal threshold and increased TG inflammation, macrophage activation, and expression of interleukin-6, cyclooxygenase-2, and substance P, while decreasing ACSL6 expression. Macrophage depletion and systemic GW4869 treatment alleviated mechanical hypersensitivity, reduced inflammatory mediator expression, and partially restored ACSL6 levels. Activated macrophage-derived CM and EXOs decreased neuronal ACSL6 expression and enhanced inflammatory responses. Inhibition of EXO release by GW4869 attenuated these effects in primary TG neurons and PC12 cells. ACSL6 overexpression and DHA supplementation independently reduced macrophage-induced neuronal inflammatory responses.

Conclusion: Macrophage-derived EXOs contribute to CFA-induced TMD pain and neuronal inflammation and are associated with reduced neuronal ACSL6 expression. ACSL6 may represent a functionally relevant downstream regulator, whereas DHA exerts an independent protective anti-inflammatory effect.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026macrophagederived,
  title = {{Macrophage-derived Exosomes Regulate Neuronal ACSL6 in Experimental Temporomandibular Disorder Pain}},
  author = {YALI ZHANG and CHENYU FAN and JINGWEN WU and SHUO MU and ZHUO CHEN and SIYU WU and XIAN WU and ZHENGUO SHEN and TIAN XING},
  journal = {In Vivo},
  year = {2026},
  month = oct,
  doi = {10.21873/invivo.14497},
  url = {https://doi.org/10.21873/invivo.14497},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Macrophage-derived Exosomes Regulate Neuronal ACSL6 in Experimental Temporomandibular Disorder Pain
AU  - YALI ZHANG
AU  - CHENYU FAN
AU  - JINGWEN WU
AU  - SHUO MU
AU  - ZHUO CHEN
AU  - SIYU WU
AU  - XIAN WU
AU  - ZHENGUO SHEN
AU  - TIAN XING
PY  - 2026
DA  - 2026/10/29
JO  - In Vivo
DO  - 10.21873/invivo.14497
UR  - https://doi.org/10.21873/invivo.14497
AB  - Background/Aim: Temporomandibular disorders (TMD) are frequently accompanied by persistent pain, but the underlying mechanisms remain incompletely understood. Macrophage-neuron communication in the trigeminal ganglion (TG) may contribute to TMD pain. This study investigated whether macrophage-derived exosomes (EXOs) promote neuronal inflammation and pain by regulating acyl-CoA synthetase long-chain family member 6 (ACSL6).  Materials and Methods: A mouse model of TMD pain was established by intra-articular injection of complete Freund’s adjuvant (CFA) into the temporomandibular joint. Pain behavior, TG histopathology, inflammatory mediator expression, and ACSL6 levels were evaluated. The effects of clodronate liposome-mediated macrophage depletion and GW4869-mediated inhibition of EXO release were examined in vivo. In vitro, conditioned medium (CM) and EXOs derived from tumor necrosis factor-alpha-activated RAW264.7 cells were applied to primary TG neurons and PC12 cells. GW4869 treatment of RAW264.7 cells, ACSL6 overexpression, and docosahexaenoic acid (DHA) supplementation were used for further functional evaluation.  Results: CFA reduced the head withdrawal threshold and increased TG inflammation, macrophage activation, and expression of interleukin-6, cyclooxygenase-2, and substance P, while decreasing ACSL6 expression. Macrophage depletion and systemic GW4869 treatment alleviated mechanical hypersensitivity, reduced inflammatory mediator expression, and partially restored ACSL6 levels. Activated macrophage-derived CM and EXOs decreased neuronal ACSL6 expression and enhanced inflammatory responses. Inhibition of EXO release by GW4869 attenuated these effects in primary TG neurons and PC12 cells. ACSL6 overexpression and DHA supplementation independently reduced macrophage-induced neuronal inflammatory responses.  Conclusion: Macrophage-derived EXOs contribute to CFA-induced TMD pain and neuronal inflammation and are associated with reduced neuronal ACSL6 expression. ACSL6 may represent a functionally relevant downstream regulator, whereas DHA exerts an independent protective anti-inflammatory effect.
SN  - 0258-851X
SN  - 1791-7549
ER  -